Successful Investigational New Drug Preparation without Reinventing the Wheel

Abstract

The biotech industry is the usual venue of new drug development, with costs estimated between $500 million and $2 billion per drug developed (Adams and Brantner, 2006Adams C.P. Brantner V.V. Estimating The cost of new drug development: is it really $802 million?.Health Aff. 2006; 25: 420-428Crossref PubMed Scopus (685) Google Scholar). Occasionally, members of an academic medical community may choose to develop a new drug within their own institution because they are focused on an orphan disease and/or their new therapy may lack a successful financial model. The Dermatology Department at Stanford University School of Medicine has focused on creating a successful treatment for epidermolysis bullosa since 1988. Support for this process has come from philanthropy (http://www.ebkids.org) as well as federal and state funding. During this process, we have learned that most academic medical centers do not prepare faculty for the challenges of developing new drugs. The focus of this Editorial and the Supplementary Material online is to review the process for beginning a clinical trial for a new drug product in the United States. Major goals include Investigational New Drug (IND) approval and completion of multiple clinical trials, with a final goal of New Drug Application (NDA) approval, allowing the drug to be prescribed, sold, and marketed within the United States (FDA, 2010aFDA Food and Drug Administration. Drug development and review definitions.http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm176522.htmDate: 2010Google Scholar, FDA, 2010bFDA Food and Drug Administration. Types of applications.http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/default.htmDate: 2010Google Scholar). Download .pdf (.2 MB) Help with pdf files Supplementary Information Drug development occurs in individual states, but because most drugs will eventually be shipped across state borders, they are under control of federal law, enforced by the US Food and Drug Administration (FDA) (FDA, 2010cFDA Food and Drug Administration. Investigational New Drug (IND) application.http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/default.htm#Date: 2010Google Scholar). An IND is the FDA exemption that allows a drug to be shipped across state lines before the NDA is approved. IND submission follows initial studies that demonstrate the drug’s safety in animals, with the goal of conducting human clinical studies to determine its therapeutic potential (FDA, 2010cFDA Food and Drug Administration. Investigational New Drug (IND) application.http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/default.htm#Date: 2010Google Scholar). During the process of obtaining an IND for gene transfer for epidermolysis bullosa, we have found that personal contact with the FDA during the concept stage allowed us to understand the submission process and the FDA to understand our goals and capabilities. FDA regulations require precise actions, but the goal of the agency’s staff is to bring the best products to patients as soon as possible. FDA staff will inform you when formal correspondence is necessary and when they can answer your queries without documentation. However, we recommend that you maintain a log of all contact with the FDA (including e-mail and telephone conversations), beginning with the first pre-IND communications. This log will help to prevent your repeating questions. IND submission requires an application to either the Center for Biologics Evaluation and Research or the Center for Drug Evaluation and Research (Table 1; FDA, 2010dFDA Food and Drug Administration. Transfer of therapeutic products to the center for drug evaluation and research.http://www.fda.gov/AboutFDA/CentersOffices/CBER/ucm133463.htmDate: 2010Google Scholar). Devices are regulated by a separate entity and require a different type of application, which is not discussed in this Editorial (FDA, 2010eFDA Food and Drug Administration. Device advice: device regulation and guidance.http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/default.htmDate: 2010Google Scholar). IND application requirements are available on the FDA’s website (FDA, 2010fFDA Food and Drug Administration. Code of Federal Regulations Title 21, Part 312—Investigational New Drug Application.http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.23Date: 2010Google Scholar)—check whether your institution has a program in place to assist with the logistics of this process. The IND application consists of four main parts, listed in the order in which they appear in the IND application: (i) Investigator’s Brochure (IB), (ii) Clinical Protocol, (iii) Chemistry, Manufacturing, and Control (CMC), and (iv) Pharmacology and Toxicology (FDA, 1995FDA Food and Drug Administration. Guidance for industry: content and format of Investigational New Drug Applications (INDs) for Phase 1 studies of drugs, including well-characterized, therapeutic, biotechnology-derived products. 1995http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071597.pdfGoogle Scholar, FDA, 2000FDA Food and Drug Administration. Guidance for industry: Q&A: content and format of INDs for Phase 1 studies of drugs, including well-characterized, therapeutic, biotechnology-derived products.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078928.pdfDate: 2000Google Scholar). INDs can be submitted in hard copy or electronically (FDA, 2002FDA Food and Drug Administration. Guidance for industry: providing regulatory submissions to CBER in electronic format—Investigational New Drug Applications (INDs).http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/General/UCM150028.pdfDate: 2002Google Scholar).Table 1Center for Biologics Evaluation and Research versus Center for Drug Evaluation ResearchFDA CenterProducts under center's jurisdictionCenter for Biologics Evaluation and ResearchCellular products composed of human, bacterial, or animal cells; gene therapy products; vaccines; allergenic extracts used for the diagnosis and treatment of allergic diseases; antitoxins, antivenins, and venoms; and blood and blood componentsCenter for Drug Evaluation and ResearchNonbiological drugs as well as monoclonal antibodies for in vivo use and proteins intended for therapeutic use, including cytokines, enzymes, growth factors, and immunomodulatorsFrom FDA, 2010dFDA Food and Drug Administration. Transfer of therapeutic products to the center for drug evaluation and research.http://www.fda.gov/AboutFDA/CentersOffices/CBER/ucm133463.htmDate: 2010Google Scholar. Open table in a new tab From FDA, 2010dFDA Food and Drug Administration. Transfer of therapeutic products to the center for drug evaluation and research.http://www.fda.gov/AboutFDA/CentersOffices/CBER/ucm133463.htmDate: 2010Google Scholar. For single-site studies in which the investigator will hold the IND, the IB is not required (FDA, 2010gFDA Food and Drug Administration. Code of Federal Regulations: 21 CFR 312.55: informing investigators.http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.55Date: 2010Google Scholar). Data from previous studies are included in the IB, which is important in determining whether an adverse event is considered “reportable” (FDA, 2009FDA Food and Drug Administration. Guidance for clinical investigators, sponsors, and IRBs: adverse event reporting to IRBs—improving human subject protection.http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126572.pdfDate: 2009Google Scholar). Clinical investigators will be most familiar with the Clinical Protocol. All human clinical trials require institutional review board (IRB) approval from the local institution. The clinical trial and recruitment efforts cannot begin until approval is granted, which is contingent on approval of the IND by the FDA. The local IRB can often help navigate FDA regulations. Each institution will most likely require completion of training requirements to work with human subjects in addition to Health Insurance Portability and Accountability Act training (FDA, 2010hFDA Food and Drug Administration. Code of Federal Regulations, Title 45, Part 46: protection of human subjects.http://ohsr.od.nih.gov/guidelines/45cfr46.htmlDate: 2010Google Scholar; National Institutes of Health, Office of Human Subjects Research, 1949National Institutes of Health, Office of Human Subjects Research Nuremberg Code, Directives for Human Experimentation.http://ohsr.od.nih.gov/guidelines/nuremberg.htmlDate: 1949Google Scholar, National Institutes of Health, Office of Human Subjects Research, 1979National Institutes of Health, Office of Human Subjects Research The Belmont Report.http://ohsr.od.nih.gov/guidelines/belmont.htmlDate: 1979Google Scholar; Stanford University). The Clinical Protocol describes the details of the clinical trial that will test the product. Clinical trials are divided into three phases: I, II, and III (Table 2; FDA, 2010hFDA Food and Drug Administration. Code of Federal Regulations, Title 45, Part 46: protection of human subjects.http://ohsr.od.nih.gov/guidelines/45cfr46.htmlDate: 2010Google Scholar). The conduct of clinical trials requires compliance with established international regulations known as “good clinical practices” (FDA, 2011aFDA Food and Drug Administration. FDA regulations relating to good clinical practice and clinical trials.http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm155713.htm#Date: 2011Google Scholar, FDA, 2011bFDA Food and Drug Administration. Running clinical trials.http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htmDate: 2011Google Scholar). For additional information on good clinical practices, including adverse-event reporting, see the Supplementary Material online. As one prepares for a trial, it may be useful to consider hiring an outside contract research organization because the complexity of the regulations may require expertise that is not common within an academic institution.Table 2Phases of clinical trialsStudy phaseGoalSubjects (characteristics, no. of subjects)Phase IDetermine the metabolic and pharmacologic actions of the drug. Determine side effectsHealthy volunteers or small number of patientsPhase IIObtain preliminary data on drug efficacySmall numbers of patientsPhase IIIGather statistically significant information about efficacy and safety of a drug. This takes place after the preliminary evidence suggests efficacy. Results will provide a basis for extrapolating results to the general population and transmitting that information in the physician labeling package for the New Drug ApplicationSeveral hundred or moreFrom FDA, 2010aFDA Food and Drug Administration. Drug development and review definitions.http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm176522.htmDate: 2010Google Scholar. Open table in a new tab From FDA, 2010aFDA Food and Drug Administration. Drug development and review definitions.http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm176522.htmDate: 2010Google Scholar. The CMC section describes the chemical formulation of the drug, how it will be manufactured, and the requisite control of these processes (e.g., purity of reagents). During a pre-IND meeting with the FDA, investigators will have an opportunity to discuss the CMC and to determine the FDA’s specific requirements for the product. There are specific requirements for drug manufacturing called good manufacturing practice or current good manufacturing practice (FDA, 2004FDA Food and Drug Administration. Guidance for industry: sterile drug products produced by aseptic processing—current good manufacturing practice.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070342.pdfDate: 2004Google Scholar; FDA, 2010iFDA Food and Drug Administration. Code of Federal Regulations, Title 21, Part 210—current good manufacturing practice in manufacturing, processing, packing, or holding of drug; general.http://www.access.gpo.gov/nara/cfr/waisidx_10/21cfr210_10.htmlDate: 2010Google Scholar, FDA, 2010jFDA Food and Drug Administration. Code of Federal Regulations, Title 21, Part 211—current good manufacturing practice for finished pharmaceuticals.http://www.access.gpo.gov/nara/cfr/waisidx_10/21cfr211_10.htmlDate: 2010Google Scholar; FDA, 2011cFDA Food and Drug Administration. Questions and answers on current good manufacturing practices (cGMP) for drugs.http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124740.htmDate: 2011Google Scholar); however, current good manufacturing practice is not required for phase I clinical trials (FDA, 2008FDA Food and Drug Administration. Guidance for industry: cGMP for Phase 1 investigational drugs.http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070273.pdf type="urlDate: 2008Google Scholar). Instead, the CMC for a phase I trial focuses on identification and control of raw materials used to manufacture the drug, as well as the drug itself (FDA, 2010fFDA Food and Drug Administration. Code of Federal Regulations Title 21, Part 312—Investigational New Drug Application.http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.23Date: 2010Google Scholar). There are also complex requirements for release criteria of the final product (FDA, 2010kFDA Food and Drug Administration. Code of Federal Regulations, Title 21, Part 610—general biological products standards.http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=610Date: 2010Google Scholar). Laboratories used for testing should abide by regulations for good laboratory practices (FDA, 2010lFDA Food and Drug Administration. Code of Federal Regulations, Title 21, Part 58: good laboratory practice for nonclinical laboratory studies.http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=58Date: 2010Google Scholar). There are additional criteria for reagents of animal origin (Department of Agriculture, 2003Department of Agriculture Code of Federal Regulations—Title 9, Volume 1.http://www.access.gpo.gov/nara/cfr/waisidx_03/9cfr113_03.htmlDate: 2003Google Scholar), biohazardous agents, and recombinant DNA, as well as gene therapy, somatic cell therapy, and stem cell therapy (Carpenter et al., 2009Carpenter M.K. Frey-Vasconcells J. Rao M.S. Developing safe therapies from human pluripotent stem cells.Nat Biotech. 2009; 27: 606-613Crossref PubMed Scopus (110) Google Scholar; Fink, 2009Fink D.W. FDA regulation of stem cell-based products.Science. 2009; 324: 1662-1663Crossref PubMed Scopus (118) Google Scholar). Please see the Supplementary Material for additional information about these special cases. The animal studies included in this section will vary widely, and they must be discussed with the FDA at the pre-IND meeting. Areas of special concern include studies involving stem cells and gene therapy. The Supplementary Material includes guidance about these topics. Although the process of applying for an IND may seem daunting, we hope that our suggestions have provided some clarification. We acknowledge that by the time this article is published, there may be additional changes to the IND submission process and even changes in the guidance documents referenced in the supplementary material. However, the priority of patient safety will remain, and the FDA is, in fact, interested in the successful development of new therapies for patients. The project described was funded by grants 5R01AR055914-02 from the National Institutes of Health and DR1-01454 from the California Institute of Regenerative Medicine and by gift funds from the Epidermolysis Bullosa Medical Research Foundation. Supplementary material is linked to the online version of the paper at http://www.nature.com/jid